Affiliations: [a]
Department of Emergency Medicine, Brain Research Laboratory, Emory University, Atlanta, Georgia, USA
| [b]
Department of Pharmacy, Jiangsu Health Vocational College, Nanjing, Jiangsu, China
| [c]
Xuzhou Medical University, Xuzhou, China
Correspondence:
[*]
Corresponding author: Donald G. Stein, 1365 B Clifton Rd NE, Suite 5100, USA. Tel.: +1 404 712 2540; Fax: +1 404 778 2630; E-mail: [email protected].
Abstract: Background:In this proof-of-concept paper, we investigated whether combination treatment with progesterone (P4) and chloroquine (CQ) would reduce ischemic injury more effectively than either agent alone in a transient middle cerebral artery occlusion (tMCAO) model in male rats. Methods:P4 (8 mg/kg) and CQ (25 mg/kg) were given alone or in combination beginning at different times during surgery and for 3 days post-occlusion. Locomotor activity and grip strength were evaluated as measures of impairment and recovery. Infarct size was assessed by TTC staining. Markers of autophagy (LC3 and SQSTM1/p62) and apoptosis (Bcl-2 and Bax) were evaluated with western blotting. Results:At the doses we employed, the combination was not more effective than either drug given separately on measures of grip strength or locomotor activity. However, combination therapy substantially reduced infarct size, and significantly increased Bcl-2 protein levels and suppressed Bax expression. Progesterone decreased the expression of LC3-II 24 h and SQSTM1/p62 after ischemia. Conclusions:Our findings suggest that combination therapy with P4 and CQ is not detrimental and has a small-to-moderate additive neuroprotective effect on ischemic injury in rats without substantively affecting behavioral outcomes. CQ and P4 may help to regulate the expression of both autophagy-related and apoptosis-related proteins.
